U.S. patent application number 16/564587 was filed with the patent office on 2019-12-26 for composition for patch preparation comprising drug, organic solvent, lipophilic mass base, and powder.
This patent application is currently assigned to MEDRX CO., LTD.. The applicant listed for this patent is MEDRX CO., LTD.. Invention is credited to Hidetoshi Hamamoto, Takahiro Tanimoto, Katsuhiro Yamanaka.
Application Number | 20190388544 16/564587 |
Document ID | / |
Family ID | 49768781 |
Filed Date | 2019-12-26 |
United States Patent
Application |
20190388544 |
Kind Code |
A1 |
Hamamoto; Hidetoshi ; et
al. |
December 26, 2019 |
Composition for Patch Preparation Comprising Drug, Organic Solvent,
Lipophilic Mass Base, and Powder
Abstract
The object of the present invention is to provide a composition
for a non-aqueous patch preparation with excellent adhesibility
which can sustainedly release a drug. The patch preparation of the
present invention can improve the adhesibility of the patch
preparation and the release property of a drug by the addition of a
powder ingredient (a filler or the like). As a result, the
long-time sustention of the adhesibility of tape preparations
enables an improvement of the transdermal absorbability and the
sustained release of a drug. By the use of a composition for a
patch preparation comprising this powder ingredient, a drug,
regardless of the type of a drug is dissolved in an organic solvent
or an ionic liquid to prepare a drug solution comprising the
organic solvent, the drug solution is incorporated into the
non-aqueous patch preparation of the present invention, and thereby
a preparation with the improved transdermal absorbability and the
improved sustained release can prepared.
Inventors: |
Hamamoto; Hidetoshi;
(Kagawa, JP) ; Yamanaka; Katsuhiro; (Kagawa,
JP) ; Tanimoto; Takahiro; (Kagawa, JP) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
MEDRX CO., LTD. |
Kagawa |
|
JP |
|
|
Assignee: |
MEDRX CO., LTD.
Kagawa
JP
|
Family ID: |
49768781 |
Appl. No.: |
16/564587 |
Filed: |
September 9, 2019 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
14408649 |
Dec 17, 2014 |
|
|
|
PCT/JP2013/066765 |
Jun 18, 2013 |
|
|
|
16564587 |
|
|
|
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/485 20130101;
A61K 38/23 20130101; A61K 31/407 20130101; A61K 47/14 20130101;
A61P 43/00 20180101; A61K 31/167 20130101; A61K 47/38 20130101;
A61K 47/18 20130101; A61K 31/7088 20130101; A61K 9/7053 20130101;
A61K 31/165 20130101; A61K 47/32 20130101 |
International
Class: |
A61K 47/18 20060101
A61K047/18; A61K 9/70 20060101 A61K009/70; A61K 31/165 20060101
A61K031/165; A61K 31/167 20060101 A61K031/167; A61K 31/407 20060101
A61K031/407; A61K 31/485 20060101 A61K031/485; A61K 38/23 20060101
A61K038/23; A61K 47/32 20060101 A61K047/32; A61K 47/38 20060101
A61K047/38 |
Foreign Application Data
Date |
Code |
Application Number |
Jun 20, 2012 |
JP |
2012-139215 |
Claims
1. A composition for a non-aqueous patch preparation comprising a
drug, an organic solvent, a lipophilic mass base, and a powder.
2. The composition according to claim 1, wherein the powder is
insoluble both in the drug solution in the organic solvent and in
the lipophilic mass base.
3. The composition according to claim 1, wherein the powder is at
least one selected from the group consisting of crystalline
cellulose, anhydrous silicic acid, starch, carmellose, carmellose
metal salt, kaolin, agar, carrageenan, pectin, powdered sugar,
polyethylene powder, and polystyrene sulfonate.
4. The composition according to claim 1 or 2, wherein the powder is
crystalline cellulose.
5. The composition according to any one of claims 1 to 4, wherein
the organic solvent comprises an ionic liquid.
6. The composition according to claim 5, wherein the ionic liquid
is an alkanolamine organic carboxylate.
7. The composition according to claim 6, wherein said organic
carboxylic acid is a combination of a higher fatty acid and an
organic carboxylic acid having 3 to 7 carbon atoms.
8. The composition according to claim 7, wherein said higher fatty
acid is a saturated or unsaturated fatty acid having 10 to 22
carbon atoms.
9. The composition according to claim 8, wherein said saturated or
unsaturated fatty acid having 10 to 22 carbon atoms is at least one
selected from the group consisting of decanoic acid, oleic acid,
isostearic acid, and myristic acid.
10. The composition according to claim 7, wherein said organic
carboxylic acid having 3 to 7 carbon atoms is a carboxylic acid
compound having a hydroxyl group and ketone group.
11. The composition according to claim 10, wherein said carboxylic
acid compound having a hydroxyl group and a ketone group is at
least one selected from the group consisting of lactic acid,
levulinic acid, and salicylic acid.
12. The composition according to claim 6, wherein said alkanolamine
is at least one selected from the group consisting of
triethanolamine, triisopropanolamine, and diisopropanolamine.
13. The composition according to claim 5, wherein said ionic liquid
is at least one selected from the group consisting of
triethanolamine lactate, triisopropanolamine lactate,
triethanolamine levulinate, diisopropanolamine levulinate,
triisopropanolamine decanoate, triethanolamine salicylate,
diisopropanolamine oleate, triethanolamine isostearate,
diisopropanolamine isostearate, and diisopropanolamine
myristate.
14. The composition according to claim 7, wherein said ionic liquid
of an alkanolamine salt of organic carboxylic acid having 3 to 7
carbon atoms is at least one selected from the group consisting of
triethanolamine lactate, triisopropanolamine lactate,
triethanolamine levulinate, diisopropanolamine levulinate,
triethanolamine salicylate, and triisopropanolamine salicylate.
15. The composition according to claim 8, wherein said ionic liquid
of an alkanolamine salt of saturated or unsaturated fatty acid
having 10 to 22 carbon atoms is at least one selected from the
group consisting of triisopropanolamine decanoate, triethanolamine
decanoate, diisopropanolamine decanoate, diisopropanolamine oleate,
triethanolamine isostearate, diisopropanolamine isostearate, and
diisopropanolamine myristate.
16. The composition according to any one of claims 1 to 15, wherein
the elastomer of said lipophilic mass base is
styrene-isoprene-styrene block copolymer.
17. The composition according to any one of claims 1 to 16, wherein
said drug is selected from a small molecular medicinal compound, a
protein medicine, an antigen peptide, or a nucleic acid derivative.
Description
TECHNICAL FIELD
[0001] The present invention relates to a composition for a patch
preparation comprising a drug, an organic solvent, a lipophilic
mass base, and a powder. Particularly, the present invention
relates to a composition for a patch preparation with the improved
drug-solubility and the improved transdermal-absorbability, wherein
the organic solvent comprises a fatty acid-based ionic liquid.
BACKGROUND ART
[0002] In order to prepare a composition for a patch preparation
comprising a drug, the process of dissolving a drug in a solvent
such as an organic solvent, mixing the drug solution with an
adhesive, and extending the mixture to prepare a composition for a
patch preparation has been generally used. In such case, the
organic solvent used therein has been employed for serving as a
transdermal absorption accelerator along with dissolving a
drug.
[0003] Recently, some attempts to use a fatty acid-based ionic
liquid as a solution for dissolving a drug or a transdermal
absorption accelerator have been made (e.g. Patent Document 1). The
ionic liquid used therein is mainly an alkanolamine salt of a fatty
acid. Thus, the development as a non-aqueous patch preparation (a
tape preparation) has been mainly studied to exert the effect of
the ionic liquid.
[0004] On the other hand, a mass base used in such non-aqueous
patch preparation (a tape preparation) is a lipophilic mass base
which has less affinity for a fatty acid based-ionic liquid with
high polarity in a salt form, and thus it has a tendency to be less
miscible with the ionic liquid. As a result, a drug solution in
which a drug is dissolved in a fatty acid based-ionic liquid alone
or an organic solvent containing a fatty acid based-ionic liquid is
less soluble and less miscible with a lipophilic mass base for a
patch preparation, and thus has a tendency to be basically
separated.
[0005] Hence, it has been known that when a non-aqueous patch
preparation (a tape preparation) is prepared by using a drug
solution prepared from a drug and an organic solvent containing a
fatty acid-based ionic liquid, the drug solution comprising the
fatty acid-based ionic liquid exudes onto the surface of the tape
preparation, which can make the adhesibility to the skin poor. In
addition, the drug solution can be encompassed into a lipophilic
mass base in the form of droplets depending on the viscosities of
the lipophilic mass base and the drug solution comprising an ionic
liquid and an organic solvent, the surfactant action of the ionic
liquid, or the amount of the ionic liquid. In such case, the
droplets are dispersed as separate vacuole, and thus the drug
solution is not released from the mass base. As a result, this
causes a variety of problems, for example, deterioration of the
release property of a drug in the patch preparation. Although a
variety of means for solving these problems have been studied until
now, any drastic means have not been found.
PRIOR ART DOCUMENTS
Patent Documents
[0006] Patent Document 1: JP 2009-066457
SUMMARY OF INVENTION
Problem to be Solved by the Invention
[0007] An object of the present invention is to provide a
composition for a non-aqueous patch preparation which suitably
disperses an organic solvent containing a drug into a lipophilic
mass base for a non-aqueous patch preparation (a tape preparation),
avoids the separate vacuolation of a drug solution, and further
improves the adhesibility of the patch preparation and the release
property of the drug. Particularly, the object is to provide a
composition for a non-aqueous patch preparation in which a solvent
containing an ionic liquid is used as an organic solvent.
Means for Solving the Problems
[0008] The present inventors have found that by adding a powder
which is insoluble both in an ionic liquid or a solvent, and in a
lipophilic mass base to a conventional non-aqueous patch
preparation (a tape preparation) comprising an ionic liquid, a drug
solution containing a drug is retained in spaces between the
powders or in spaces between the powder and the mass base, and thus
the drug solution is not released from the mass base. As a result,
the present inventors have found that the drug solution does not
uselessly exude onto the surface of the patch preparation, and thus
the adhesibility of the patch preparation can be improved. In
addition, the present inventors have found that the drug solution
retained in the spaces between the powders or in the spaces between
the powder and the mass base as described above can gradually
transfer to the surface of the mass base via each space, and thus
the release property of the drug can be improved. Also, even when
an ionic liquid is encompassed into a lipophilic mass base as
droplets, the drug solution can be released onto the surface of the
mass base via the spaces between the powders or the spaces between
the powder and the mass base which are formed by the addition of
the powder, and thus the release property of the drug can be
improved.
[0009] Furthermore, the present inventors have studied a variety of
powders which could easily form the spaces between the powders or
the spaces between the powder and the mass base, and then have
found that inorganic fillers or organic reagents such as starch,
crystalline cellulose, and agar which are contained in the patch
preparation can produce useful effects. In addition, the present
inventors have found that the sustained release of a drug can be
achieved by a combination of these powders.
[0010] The present inventors have completed the present invention
on the basis of the above findings.
[0011] The subject matters of the present invention are as follows.
[0012] (1) A composition for a non-aqueous patch preparation
comprising a drug, an organic solvent, a lipophilic mass base, and
a powder. [0013] (2) The composition according to the above item
(1), wherein the powder is insoluble both in the drug solution in
the organic solvent and in the lipophilic mass base. [0014] (3) The
composition according to the above item (1), wherein the powder is
at least one selected from the group consisting of crystalline
cellulose, anhydrous silicic acid, starch, carmellose, carmellose
metal salt, kaolin, agar, carrageenan, pectin, powdered sugar,
polyethylene powder, and polystyrene sulfonate. [0015] (4) The
composition according to the above item (1) or (2), wherein the
powder is crystalline cellulose. [0016] (5) The composition
according to any one of the above items (1) to (4), wherein the
organic solvent comprises an ionic liquid. [0017] (6) The
composition according to the above item (5), wherein the ionic
liquid is an alkanolamine organic carboxylase. [0018] (7) The
composition according to the above item (6), wherein said organic
carboxylic acid is a combination of a higher fatty acid and an
organic carboxylic acid having 3 to 7 carbon atoms. [0019] (8) The
composition according to the above item (7), wherein said higher
fatty acid is a saturated or unsaturated fatty acid having 10 to 22
carbon atoms. [0020] (9) The composition according to the above
item (8), wherein said saturated or unsaturated fatty acid having
10 to 22 carbon atoms is at least one selected from the group
consisting of decanoic acid, oleic acid, isostearic acid, and
myristic acid. [0021] (10) The composition according to the above
item (7), wherein said organic carboxylic acid having 3 to 7 carbon
atoms is a carboxylic acid compound having a hydroxyl group and a
ketone group. [0022] (11) The composition according to the above
item (10), wherein said carboxylic acid compound having a hydroxyl
group and a ketone group is at least one selected from the group
consisting of lactic acid, levulinic acid, and salicylic acid.
[0023] (12) The composition according to the above item (6),
wherein said alkanolamine is at least one selected from the group
consisting of triethanolamine, triisopropanolamine, and
diisopropanolamine. [0024] (13) The composition according to the
above item (5), wherein said ionic liquid is at least one selected
from the group consisting of triethanolamine lactate,
triisopropanolamine lactate, triethanolamine levulinate,
diisopropanolamine levulinate, triisopropanolamine decanoate,
triethanolamine salicylate, diisopropanolamine oleate,
triethanolamine isostearate, diisopropanolamine isostearate, and
diisopropanolamine myristate. [0025] (14) The composition according
to the above item (7), wherein said ionic liquid of an alkanolamine
salt of organic carboxylic acid having 3 to 7 carbon atoms is at
least one selected from the group consisting of triethanolamine
lactate, triisopropanolamine lactate, triethanolamine levulinate,
diisopropanolamine levulinate, triethanolamine salicylate, and
triisopropanolamine salicylate. [0026] (15) The composition
according to the above item (8), wherein said ionic liquid of an
alkanolamine salt of saturated or unsaturated fatty acid having 10
to 22 carbon atoms is at least one selected from the group
consisting of triisopropanolamine decanoate, triethanolamine
decanoate, diisopropanolamine decanoate, diisopropanolamine oleate,
triethanolamine isostearate, diisopropanolamine isostearate, and
diisopropanolamine myristate. [0027] (16) The composition according
to any one of the above items (1) to (15), wherein the elastomer of
said lipophilic mass base is styrene-isoprene-styrene block
copolymer. [0028] (17) The composition according to any one of the
above items (1) to (16), wherein said drug is selected from a small
molecular medicinal compound, a protein medicine, an antigen
peptide, or a nucleic acid derivative.
EFFECTS OF THE INVENTION
[0029] The composition for a non-aqueous patch preparation of the
present invention relates to a non-aqueous patch preparation (a
tape preparation) comprising a drug solution in which a drug is
dissolved in an organic solvent and an ionic liquid, a lipophilic
mass base, and a powder. By the addition of the powder, said drug
solution with high polarity can be retained in the spaces between
the powders formed in the lipophilic mass base to avoid releasing
the drug solution from the lipophilic mass. As a result, the
deterioration of the adhesibility of the tape preparation can be
prevented. In addition, the release property and the effective
utilization ratio of a drug can be improved because the routes for
releasing the drug solution out of the mass base via said spaces
are made.
[0030] As described above, the release property of a drug which has
been a problem in conventional tape preparations can be greatly
improved, and also the adhesibility of tape preparations can be
improved. Thus, such long-time sustention of the adhesibility of
tape preparations enables the improvement of the transdermal
absorbability and the sustained release of a drug. In addition, the
effective utilization ratio of a drug can be improved along with
the sustained release of a drug because the drug solution in the
mass base gradually exudes onto the surface of the mass base via
the spaces between the powders.
BRIEF DESCRIPTION OF DRAWINGS
[0031] FIG. 1 is a conceptual diagram showing a cross-section of
the mass base in the non-aqueous patch preparation (the tape
preparation) of the present invention. FIG. 1 shows that the powder
is dispersed into the lipophilic mass base (the oil-soluble mass
base), and the drug solution is retained in the spaces between the
powders or in the spaces between the powder and the mass base.
Furthermore, FIG. 1 shows that quite-narrow channels for releasing
the drug solution from the inside of the mass base onto the surface
of the mass base are formed by connecting these spaces to each
other. The parts in which the powder is present on the surface of
the mass base cause the exudation of the drug solution from the
spaces around the powder, whereas the parts in which the powder is
not present on the surface of the mass base cause less exudation or
less release of the drug solution. As result, the deterioration of
the adhesibility of the patch preparation is prevented as a whole.
FIG. 1 also shows the above.
DESCRIPTION OF EMBODIMENTS
[0032] The term "drug" in the present invention denotes a drug for
medical use selected from a small molecular medicinal compound, a
protein medicine, an antigen peptide, or a nucleic acid derivative.
Many of the drugs used in the present invention have hydrophilic
residue(s) as a main substituent (or drugs in a salt form).
Thereby, such drugs are less soluble in a lipophilic mass base.
Thus, an ionic liquid with high polarity is used to dissolve the
drug, and the solution of the drug in an ionic liquid is used as a
drug solution. Among the drugs of the present invention, for
example, a small molecular medicinal compound denotes a drug that
exhibits acidity ("acidic drug") or a drug that exhibits basicity
("basic drug").
[0033] The term "acidic drug" herein denotes a drug which has a
carboxylic acid as a functional group and exhibits acidity as a
whole of the compound. Examples of the acidic drug include
non-steroid anti-inflammatory drugs (NSAIDs) such as indomethacin,
ketoprofen, ibuprofen, flurbiprofen, diclofenac, etodolac, and
loxoprofen; anti-allergic drugs such as tranilast, cromoglicic
acid, and pemirolast; sedative hypnotic drugs or anti-anxiety drugs
such as amobarbital, secobarbital, and phenobarbital; and muscle
relaxant drugs such as dantrolene, and mivacurium.
[0034] Preferred examples of the acidic drug include indomethacin,
flurbiprofen, ketoprofen, etodolac, ibuprofen, loxoprofen, and
diclofenac.
[0035] The term "basic drug" in the present invention denotes a
drug which has a primary, secondary, or tertiary amine structure as
a functional group and exhibits basicity as a whole of the
compound. Examples of the basic drug include topical anesthetic
drugs such as lidocaine, dibucaine, bupivacaine, procaine,
mepivacaine, bupivacaine, and tetracaine; anti-histamine drugs such
as diphenhydramine; analgesic drugs such as tramadol;
anti-spasmodic drugs such as eperisone; muscle relaxant drugs such
as tolperisone; antitussive drugs such as dextromethorphan;
acetylcholine decomposition inhibitors such as donepezil; and
opioid analgesic drugs such as morphine, codeine, naloxone,
fentanyl, and oxycodone. Preferred examples of the basic drug
include lidocaine, tolperisone, bupivacaine, eperisone, tramadol,
morphine, and donepezil.
[0036] The term "protein medicine" in the present invention denotes
a protein for medical use. Examples of the protein medicine include
various recombinant proteins and modified proteins which are
relatively small molecules. Examples of various recombinant
proteins and modified proteins include insulin, human growth
hormone, elcatonin, calcitonin, EGF, VEGF, and GLP-1.
[0037] The term "antigen peptide" in the present invention denotes
an antigenic fragment derived from a foreign microbe or a tumor
cell which is used for stimulating immunity. Examples of the
antigen peptide include WT-1, and human papillomavirus.
[0038] The term "nucleic derivative" in the present invention
denotes a general term for DNA and RNA which are used as a
medicinal ingredient. The DNA used herein is not especially limited
as long as it is DNA for gene therapy. Examples of the nucleic
derivative include DNA vaccine, antisense, ribozyme, aptamer, and
siRNA.
[0039] The term "ionic liquid" in the present invention denotes a
Bronsted salt prepared from a compound having carboxyl group(s) (an
organic carboxylic acid) and an amine compound, which is in a
viscous liquid form at ordinary temperature. Preferably, the amine
compound is an alkanolamine.
[0040] The term "organic carboxylic acid" in the present invention
denotes a higher fatty acid, an organic carboxylic acid having 3 to
7 carbon atoms, and a mixture thereof. Furthermore, the organic
carboxylic acid-based ionic liquid denotes an alkanolamine salt of
said organic carboxylic acid, that is, an alkanolamine salt of said
higher fatty acid, an alkanolamine salt of said organic carboxylic
acid having 3 to 7 carbon atoms, and a mixture thereof.
[0041] Preferably, in order to enhance the skin permeability of the
drug, the organic carboxylic acid-based ionic liquid used in the
drug solution is in the state that the drug solubility of the drug
solution is close to saturation. Hence, the drug solubility of the
drug solution can be controlled through a combination of the
organic carboxylic acid-based ionic liquids and/or the selected
solvent. For example, the drug solubility of the drug solution can
be controlled by evaluating each drug solubility of the
alkanolamine salt of said higher fatty acid and the alkanolamine
salt of said organic carboxylic acid having 3 to 7 carbon atoms,
and then mixing said salts.
[0042] The term "higher fatty acid" in the present invention
denotes a saturated or unsaturated aliphatic carboxylic acid having
10 to 22 carbon atoms. Examples of the higher fatty acid include
decanoic acid, oleic acid, and isostearic acid. Also, one or more
of the higher fatty acids may be used in combination.
[0043] The term "organic carboxylic acid having 3 to 7 carbon
atoms" in the present invention denotes a C.sub.3-7 carboxylic acid
compound having hydroxyl group(s) and ketone group(s). Examples of
the organic carboxylic acid having 3 to 7 carbon atoms include
lactic acid, levulinic acid, and salicylic acid. Also, one or more
of the organic carboxylic acids may be used in combination.
[0044] The term "alkanolamine" in the present invention denotes an
alkanolamine having 4 to 12 carbon atoms. Examples of the
alkanolamine include diethanolamine, triethanolamine,
diisopropanolamine, and triisopropanolamine.
[0045] The organic carboxylic acid-based ionic liquid of the
present invention comprises an equilibrium mixture of each
equimolar amount of an organic carboxylic acid and an amine
compound along with a Bronsted salt. Preferred examples of the
organic carboxylic acid-based ionic liquid of the present invention
include triethanolamine lactate, triisopropanolamine lactate,
triethanolamine salicylate, triisopropanolamine salicylate,
triisopropanolamine decanoate, triethanolamine decanoate,
diisopropanolamine decanoate, diisopropanolamine oleate,
triethanolamine isostearate, diisopropanolamine isostearate, and a
mixture thereof.
[0046] The term "drug solution" in the present invention denotes a
solution in which a main drug (a drug) is dissolved in an organic
solvent. Also, the drug solution denotes a solution further
comprising an ionic liquid as a solubilizing agent of the drug or a
transdermal absorption accelerator. The drug solution of the
present invention typically comprises an ionic liquid with high
drug solubility. Also, the organic solvent used therein is required
to be miscible with the ionic liquid. Thus, a polar organic solvent
can be typically used. For example, alcohols such as propylene
glycol and/or esters such as diethyl sebacate and isopropyl
myristate can be used. The drug solution of the present invention
tends to be not so soluble in a lipophilic mass base (an
oil-soluble mass base).
[0047] The term "powder" in the present invention denotes a solid
powdered reagent which is insoluble and immiscible both in a drug
solution and in a lipophilic mass base (an oil-soluble mass base).
That is, the powder is a solid powdered reagent which is insoluble
in a solvent such as an organic solvent in the drug solution even
though the powder swells due to absorption of it. Examples of the
powder include solid powdered reagents (fillers) used in a mass
base in a patch preparation such as anhydrous silicic acid,
crystalline cellulose, zinc oxide, titanium oxide, kaolin, and
calcium carbonate. Furthermore, examples of the powder include
flour, starch powder such as corn starch, carmellose, carmellose
metal salt, agar, carrageenan, pectin, powdered sugar, polyethylene
powder, and polystyrene sulfonate. Preferred examples of the powder
include crystalline cellulose, anhydrous silicic acid, starch,
carmellose, and carmellose metal salt. The adhesibility of the
patch preparation is improved with increasing the amount of the
powder of the present invention. Meanwhile, when the powder is
excessive in amount, the patch preparation becomes hard, and
deteriorates the adhesibility of the patch preparation. The amount
of the powder to be added is preferably 1-10% by weight, more
preferably 2-6% by weight. Furthermore, in light of the spaces
formed by the powder in the mass base, the powder to be added may
be large in amount when the drug solution is presented in large
amounts, or the powder to be added may be small in amount when the
drug solution is presented in small amounts. For example, when the
amount of the drug solution is assumed as 1, the amount of the
powder can be preferably in the range of 0.1 to 0.4.
[0048] The spaces to be formed can be properly controlled by
combining various powders having different bulk density. Thus,
suitable combination of the powders can be prepared responding to
the amounts of the mass base and the organic solvent. For example,
the powder such as light anhydrous silicic acid, corn starch, and
crystalline cellulose may be used in combination.
[0049] The term "powder which is insoluble both in the drug
solution and in the lipophilic mass base" in the present invention
means that a powder is insoluble both in an organic solvent and an
ionic liquid, and in a lipophilic mass base so that the spaces
between the powders formed in the lipophilic mass base can be
retained. The term "insoluble" is used in the sense of
insolubility, and means that 1 mg of a powder cannot be dissolved
in 10 g of an organic solvent or a lipophilic mass base, according
to the definition of solubility in U.S. (U.S. Pharmacopeia National
Formulary).
[0050] The term "organic solvent" in the present invention denotes
a solvent that is miscible with an ionic liquid, which is used for
preparing a drug solution in which a drug is dissolved in
combination with the ionic liquid. The organic solvent in the
present invention can be used as a transdermal absorption
accelerator. Furthermore, the organic solvent can be used for
dispersing the organic carboxylic acid-based ionic liquid in which
a drug is dissolved into the mass base. Examples of the organic
solvent in the present invention include alcohols such as ethanol,
propanol, and glycol alcohol; polyalcohols such as ethylene glycol,
propylene glycol, 1,3-butanediol, polyethylene glycol (macrogol),
and glycerin; and esters such as diethyl sebacate, isopropyl
myristate, propylene carbonate, and diisopropyl adipate. These
organic solvents may be used in suitable combination to achieve the
above purposes. More preferably, polyalcohols such as propylene
glycol, 1,3-butanediol, and polyethylene glycol can be used in
combination with esters such as diethyl sebacate, isopropyl
myristate, and propylene carbonate.
[0051] The term "lipophilic mass base" in the present invention
denotes a mass base (an adhesive) comprising a lipophilic
macromolecule as a main component. The mass base is composed of an
elastomer and a lipophilic (hydrophobic) adhesive, in which a drug
solution is dispersed or emulsified. When the mass base is composed
of an elastomer and a lipophilic (hydrophobic) adhesive, it can be
used as a non-aqueous tape preparation (a plaster). When the mass
base is composed of an elastomer and a hydrophilic adhesive, it can
be used as an aqueous patch preparation (a cataplasm). As described
above, the lipophilic mass base is composed of an elastomer, a
tackifier, a softening filer, and the like.
[0052] Examples of the elastomer include synthetic rubbers such as
styrene-isoprene-styrene copolymer (SIS), silicon rubbers,
polyisobutylene, polystyrene-butadiene copolymer, and
polyisobutylene; acrylic acid resins such as alkyl acrylate and
alkyl methacrylate; and natural rubbers.
[0053] The tackifier denotes a reagent which can be added into the
elastomer such as a SIS resin to enhance the adhesibility of a
patch preparation to the skin. Examples of the tackifier include a
polyterpene resin, a polyolefin resin (Plastibase.RTM., and the
like) , a polystyrene resin, an aromatic petroleum resin, rosin,
and hydrogenated rosin. Preferred examples of the tackifier include
a polyterpene resin and a polyolefin resin (Plastibase.RTM., and
the like).
[0054] The softening agent is a reagent which can be added to make
the elastomer such as SIS resin and the adhesive flexible. Examples
of the softening agent include petroleum-based softening agents
such as polybutene, polyisobutylene, and process oil; fatty
oil-based softening agents such as palm oil and castor oil;
purified lanolin; and liquid paraffin. Preferred examples of the
softening agent include polybutene and liquid paraffin.
[0055] The patch preparation of the present invention may further
comprise additives such as an antioxidant, a surfactant, a
thickening agent, and a surfactant as long as the effects of the
present invention are not prevented. As the suitable additives,
commercially available reagents may be used for any purpose.
[0056] Examples of the antioxidant include organic antioxidants
such as BHT, propyl gallate, and sodium ascorbate; and inorganic
antioxidants such as sodium thiosulfate, sodium bisulfite, sodium
sulfite, and sodium pyrosulfite.
[0057] In addition, a thickening agent such as Carbopol.RTM., an
ultraviolet absorbing agent, and/or powders may be added.
[0058] Examples of the surfactant can include a non-ionic
surfactant, an anionic surfactant, a cationic surfactant, and an
amphoteric surfactant. Examples of the non-ionic surfactant include
sorbitan monolaurate, sorbitan monopalmitate, sorbitan
sesquioleate, glycerin monostearate, decaglyceryl monolaurate,
hexaglycerin polyricinoleate, polyoxyethylene (9) lauryl ether,
polyoxyethylene (2) lauryl ether, polyoxyethylene (4,2) lauryl
ether, polyoxyethylene (5) nonylphenyl ether, polyoxyethylene (7,5)
nonylphenyl ether, polyoxyethylene (10) nonylphenyl ether,
polyoxyethylene (3) octylphenyl ether, polyoxyethylene (10)
octylphenyl ether, polyoxyethylene (10) oylelamine, polyoxy (5)
oleylamine, polyoxy (5) oleic amide, polyoxyethylene (2)
monolaurate, monoglyceride stearate, and polyoxyethylene castor oil
(hydrogenated castor oil).
[0059] Examples of said anionic surfactant include sodium lauryl
sulfate, potassium lauryl sulfate, triethanolamine lauryl sulfate,
sodium cetyl sulfate, sodium lauroyl sarcosinate, sodium
di-2-ethylhexyl sulfosuccinate, sodium polyoxyethylene (10) lauryl
ether phosphate, sodium polyoxyethylene (4) lauryl ether phosphate,
sodium polyoxyethylene (5) cetyl ether phosphate, and sodium
polyoxyethylene (6) oleyl ether phosphate.
[0060] Examples of said cationic surfactant include stearyl
trimethylammonium chloride, distearyl dimethylammonium chloride,
benzalkonium chloride, and stearyl dimethyl benzylammonium
chloride.
[0061] Examples of said amphoteric surfactant include betaine
lauryldimethylaminoacetate and
2-alkyl-N-carboxymethyl-N-hydroxyethyl imidazolinium betaine. In
addition to the above, lauroyl diethanolamide can also be used.
[0062] In addition, a thickening agent such as Carbopol.RTM., an
ultraviolet absorbing agent, and/or powders may be added.
[0063] The term "patch preparation" in the present invention
denotes a non-aqueous patch preparation (a tape preparation) which
does not contain water as an essential ingredient. As the mass base
in the patch preparation of the present invention, conventional
bases, for example, an acrylic acid resin base, or a base of a SIS
resin which contains a tackifier, a softening agent and the like
can be used. Preferred examples of the base include a base in which
a SIS resin is used as an elastomer.
[0064] As a method for preparing the patch preparation of the
present invention, methods similar to those for adhesive tapes may
be adopted. Examples of the method include a solvent-coating
method. Said solvent-coating method is a method which comprises
preparing a mass base composition comprising a drug (a drug
solution), and coating the composition directly on a backing
support body followed by drying. Also, a method can be used which
comprises once coating said mass base composition on a release
paper followed by drying, and then removing the paper followed by
contact-pressing the composition on the paper to the backing.
[0065] Said release paper can be used for protecting the adhesive
layer. As examples of the paper, a polyethylene-coated quality
paper, a polyolefin-coated glassine paper, a polyethylene
terephthalate (hereinafter referred to as PET) film, a
polypropylene film or the like, one side of which is treated with
silicon, may be used.
EXAMPLES
[0066] Hereinafter, the present invention will be described more
specifically with reference to Examples. However, the present
invention is not intended to be limited to them by any means.
Example 1
Improvement of the Drug Release Property of Non-Aqueous Patch
Preparation (Tape Preparation) by Addition of Powder
[0067] a) Addition of Powder to Preparation in which Deterioration
of the Release Property is Caused by Separate Vacuolation of Drug
Solution (A)
[0068] Preparation Examples 1 and 2 are patch preparations
comprising a drug solution consisting of only a drug and an ionic
liquid. In order to make it easy to detect the release property of
a drug, brilliant blue FCF was used as an alternative to the drug.
The reagents were weighed according to the composition (part by
weight) in Table 1 below to prepare the tape preparations for
evaluation.
[0069] Specifically, brilliant blue FCF was dissolved in
triethanolamine lactate, and then diisopropylamine isostearate was
added thereto and mixed to prepare the drug solution. Following the
conventional solvent method using toluene as a solvent, terpene
resin, styrene-isoprene-styrene copolymer, butylhydroxytoluene, and
liquid paraffin were dissolved in toluene, and then the drug
solution was added thereto and mixed. Next, corn starch or light
anhydrous silicic acid was added thereto and mixed, and then each
mixture was coated on the silicone-coated PET film and dried. After
removal of the toluene, the backing was laminated to prepare the
preparations.
[0070] The prepared tape preparations were tested on the release
property of brilliant blue FCF from the mass base. Specifically,
the tape preparations of Preparation Examples 1 and 2 and
Comparison Example 1 were cut into 3.times.3 cm, dipped into a
beaker containing 8 mL of purified water, and then incubated at
32.degree. C. for 6 hours. Next, the emission of the blue pigment
from the tape preparations of the examples was measured by the
absorption spectrum measurement method at the wavelength of 630 nm.
The results are also shown in Table 1 below.
TABLE-US-00001 TABLE 1 Preparation Preparation Comparison Example 1
Example 2 Example 1 Brilliant Blue FCF 0.016 0.016 0.016 Ionic
Liquid: Triethanolamine 12 12 12 Lactate Diisopropanolamine 8 8 8
Isostearate Lipophilic Mass Base: Terpene Resin 36 36 36
Styrene-Isoprene- 20 20 20 Styrene Copolymer Antioxidant: 13 13 13
Liquid Paraffin Butylhydroxytoluene 1 1 1 Powder: Corn Starch 10
Light Anhydrous 3 Silicic Acid Release Test: 0.119 0.348 0.025
Amount of Emission (Absorbance/ Measurement Wavelength 630 nm)
[0071] As shown in the above Table 1, the release property of the
drug solution in the preparations of Preparation Examples 1 and 2
comprising the powder was improved by about 5 to 12 times as
compared to that of the preparation of Comparison Example 1 without
the powder. Also, the result suggests that anhydrous silicic acid
can make a larger contribution to the spaces and the like as a
powder than corn starch, and produce a greater release property of
the drug solution.
b) Addition of Powder to Preparation in which Deterioration of the
Release Property is Caused by Separate Vacuolation of Drug Solution
(B)
[0072] As with the above a), in order to make it easy to detect the
release property of a drug, brilliant blue FCF was used as an
alternative to the drug. The reagents were weighed according to the
composition (part by weight) in Table 2 below to prepare the tape
preparations for evaluation.
[0073] Specifically, brilliant blue FCF was dissolved in
triethanolamine lactate, and then macrogol 400 was added thereto
and mixed to prepare a drug solution. Following the conventional
solvent method using toluene as a solvent, terpene resin,
styrene-isoprene-styrene copolymer, butyihydroxytoluene, and liquid
paraffin were dissolved in toluene, and then the drug solution was
added thereto and mixed. Next, crystalline cellulose or light
anhydrous silicic acid was added thereto and mixed, and then each
mixture was coated on the silicone-coated PET film and dried. After
removal of the toluene, the backing was laminated to prepare the
preparations.
[0074] The prepared tape preparations were tested on the release
property of brilliant blue FCF from the mass base. Specifically,
the preparations of Preparation Examples 3 and 4 and Comparison
Example 2 were cut into 3.times.3 cm, dipped into a beaker
containing 8 mL of purified water, and then incubated at 32.degree.
C. for 6 hours. Next, the emission of the blue pigment from the
tape preparations of the examples was measured by the absorption
spectrum measurement method at the wavelength of 630 nm. The
results are also shown in Table 2 below.
TABLE-US-00002 TABLE 2 Preparation Preparation Comparison Example 3
Example 4 Example 2 Brilliant Blue FCF 0.016 0.016 0.016 Ionic
Liquid: Triethanolamine 6 6 6 Lactate Organic Solvent: Macrogol 400
14 14 14 Lipophilic Mass Base: Terpene Resin 38 38 38
Styrene-Isoprene- 20 20 20 Styrene Block Copolymer Antioxidant: 17
17 17 Liquid Paraffin Butylhydroxytoluene 1 1 1 Powder: Crystalline
4 cellulose Light Anhydrous 4 Silicic Acid Release Test: 0.027
0.356 0.005 Amount of Emission (Absorbance/Measurement Wavelength
630 nm)
[0075] Comparing the above Table 2 with Table 1, as shown in
Comparison Examples 1 and 2, the release properties of the drug
solutions greatly varied with the conditions such as the difference
in the composition of the ionic liquid and the presence or absence
of the organic solvent. On the other hand, as shown in Preparation
Examples 2 and 4, the release properties of the drug solutions in
the preparations comprising anhydrous silicic acid as the powder
were almost identical. The results suggest that the drug solution
can be released from the mass base without big influence, by mixing
the powder (anhydrous silicic acid) to form the spaces in the mass
base, even though the way to incorporate the drug solution into the
mass base varies with the conditions such as the different
composition of the ionic liquid, and the presence or absence of the
organic solvent.
[0076] Also, the release property of the preparation comprising
crystalline cellulose as the powder was shown to be improved by
about 5 times as compared to that of the preparation without the
powder.
Example 2
Improvement of the Adhesibility on Non-Aqueous Patch Preparation
(Tape Preparation) by Addition of Powder
[0077] a) Addition of Powder to Preparation whose Adhesibility is
Reduced and which Loosely Releases Drug Solution from Mass Base
(A)
[0078] Preparation Examples 5 and 6 are patch preparations
comprising only the ionic liquid without any drug, i.e., the
preparations are prepared as a placebo because they are only for
the evaluation about the adhesibility. The reagents were weighed
according to the composition (part by weight) in Table 3 below to
prepare the tape preparations for evaluation.
[0079] Specifically, triethanolamine lactate, triisopropanolamine
lactate, diisopropanolamine isostearate, triisopropanolamine
decanoate, triethanolamine salicylate, macrogol 400, and propylene
carbonate were mixed to prepare the drug solution. Following the
conventional solvent method using toluene as a solvent,
styrene-isoprene-styrene copolymer, isopropyl myristate,
butylhydroxytoluene, terpene resin, polybutene, and liquid paraffin
were dissolved in toluene, and then the drug solution was added
thereto and mixed. Next, light anhydrous silicic acid or
crystalline cellulose was added thereto and mixed, and then each
mixture was coated on the silicone-coated PET film and dried. After
removal of the toluene, the backing was laminated to prepare the
preparations.
TABLE-US-00003 TABLE 3 Preparation Preparation Comparison Example 5
Example 6 Example 3 Ionic Liquid: Triethanolamine 6 6 6 Lactate
Triisopropanolamine 1 1 1 Lactate Diisopropanolamine 10 10 10
Isostearate Triisopropanolamine 2 2 2 Decanoate Triethanolamine 1 1
1 Salicylate Organic Solvent: Macrogol 400 2 2 2 Propylene 5 5 5
Carbonate isopropyl 20 20 20 Myristate Antioxidant:
Butylhydroxytoluene 1 1 1 Lipophilic mass Base: Terpene Resin 24 24
24 Polybutene 1 1 1 Styrene-Isoprene- 14 14 14 Styrene Block
Copolymer Liquid Paraffin 8 8 8 Powder: Light Anhydrous 5 Silicic
Acid Crystalline 5 Cellulose
b) Addition of Powder to Preparation whose Adhesibility is Reduced
and which Loosely Releases Drug Solution from Mass Base (B)
[0080] As described above, the tape preparation of Preparation
Example 7 was prepared to evaluate the adhesibility as described
above, which had a different composition of the ionic liquid from
that of Example 1. The reagents were weighed according to the
composition (part by weight) in Table 4 below to prepare the tape
preparations for evaluation.
[0081] Specifically, triethanolamine levulinate,
triisopropanolamine levulinate, diisopropanolamine isostearate,
triisopropanolamine decanoate, triethanolamine salicylate, macrogol
400, and propylene carbonate were mixed to prepare the drug
solution. Following the conventional solvent method using toluene
as a solvent, styrene-isoprene-styrene copolymer, isopropyl
myristate, butylhydroxytoluene, terpene resin, polybutene, and
liquid paraffin were dissolved in toluene, and then the drug
solution was added thereto and mixed. Next, light anhydrous silicic
acid or crystalline cellulose was added thereto and mixed, and then
each mixture was coated on the silicone-coated PET film and dried.
After removal of the toluene, the backing was laminated to prepare
the preparations.
TABLE-US-00004 TABLE 4 Preparation Comparison Example 7 Example 4
Ionic Liquid: Triethanolamine Levulinate 6 6 Triisopropanolamine
Levulinate 1 1 Diisopropanolamine Isostearate 10 10
Triisopropanolamine Decanoate 2 2 Triethanolamine Salicylate 1 1
Organic Solvent: Macrogol 400 2 2 Propylene Carbonate 5 5 Isopropyl
Myristate 20 20 Antioxidant: Butylhydroxytoluene 1 1 Lipophilic
Mass Base: Terpene Resin 24 24 Polybutene 1 1
Styrene-Isoprene-Styrene Block 14 14 Copolymer Liquid Paraffin 8 8
Power: Crystalline Cellulose 5
c) Results of Test for Evaluating the Adhesibility
[0082] The adhesibility test was performed following the ball tack
test as defined by JIS. The patch preparation is deemed to have
sufficient adhesibility when stopping ball No. 4. Thus, the ball
tack test was performed using ball No. 4. Preparation Examples 5, 6
and 7 as well as Comparison Examples 3 and 4 were tested as test
samples. The results are shown in Table 5 below.
TABLE-US-00005 TABLE 5 Stopping of Steel Ball No. 4 Preparation
Example 5 Stopped Preparation Example 6 Stopped Preparation Example
7 Stopped Comparison Example 3 Not stopped Comparison Example 4 Not
stopped
[0083] The above preparations of Comparison Examples 3 and 4 were
beginning to loosely release the drug solution on the surface of
the mass base in the patch preparations, and thereby it was
observed that the adhesibility of the patch preparations was
deteriorated. On the other hand, the preparations of Preparation
Examples 5 and 7 comprising the powder did not cause the phenomenon
such as the loose exudation of the drug solution. Thus, it was
shown that the adhesibility of the preparation examples was not
deterirated.
Example 3
Improvement of the Transdermal Absorbability and Adhesibility of
Non-Aqueous Patch Preparation (Tape Preparation) Comprising
Oxycodone Hydrochloride, Organic Solvent Containing Ionic Liquid,
and Powder
a) Improvement of the Transdermal Absorbability
[0084] The transdermal absorbability of the tape preparation is
supposed to be improved by the improvement of the release property
of the drug from the mass base of the tape preparation. In order to
confirm it, the reagents were weighed according to the composition
(part by weight) in
[0085] Table 6 below to prepare tape preparations comprising
oxycodone hydrochloride as the drug.
[0086] Specifically, oxycodone hydrochloride trihydrate was used as
the drug, and decanoic acid, isostearic acid, myristic acid, oleic
acid, and diisopropanolamine were mixed to prepare a combined ionic
liquid. To the combined ionic liquid were added macrogol 400,
propylene carbonate, ascorbic acid, and oxycodone hydrochloride
hydrate to prepare the drug solution. Following the conventional
solvent method using toluene as a solvent, styrene-isoprene-styrene
copolymer, diethyl sebacate, isopropyl myristate,
butylhydroxytoluene, terpene resin, polybutene, liquid paraffin,
and gel hydrocarbon were dissolved in toluene, and then the drug
solution was added thereto and mixed. Next, light anhydrous silicic
acid was added thereto and mixed, and then each mixture was coated
on the silicone-coated PET film and dried. After removal of the
toluene, the backing was laminated to prepare the preparations.
[0087] The skin permeability test on the prepared tape preparations
was performed using a Franz Cell. The results are also shown in
Table 6.
TABLE-US-00006 TABLE 6 Preparation Comparison Example 8 Example 5
Oxycodone Hydrochloride Hydrate 2.3070 2.3070 Ionic Liquid:
Decanoic Acid 0.975 0.975 Isostearic Acid 6.00 6.00 Myristic Acid
0.40 0.40 Oleic Acid 0.80 0.80 Diisopropanolamine 1.646 1.646
Organic Solvent: Propylene Glycol 14.50 14.50 Propylene Carbonate
10.00 10.00 Diethyl Sebacate 5.00 5.00 Isopropyl Myristate 3.00
3.00 Antioxidant: Butylhydroxytoluene 1.00 1.00 Ascorbic acid 0.10
0.10 Lipophilic Mass Base: Terpene Resin 27.00 27.00
Styrene-Isoprene-Styrene 15.00 15.00 Block Copolymer Gel
Hydrocarbon 5.00 5.00 Liquid Paraffin 3.272 3.272 Powder: Light
Anhydrous Silicic Acid 4.00 0.00 Total (%) 100.000 96.000 Skin
Permeation Amount (.mu.g/cm.sup.2) Two hours 64.8 40.2 Four hours
160.3 121.9
b) Improvement of the Adhesibility of Preparation
[0088] The adhesibility test was performed following the ball tack
test as defined by JIS. The ball tack test was performed using
variously-numbered balls. Preparation Example 8 and Comparison
Example 5 were tested as test samples. The results are shown in
Table 7 below.
TABLE-US-00007 TABLE 7 Number of Ball Preparation Example 8
Comparison Example 5 No. 1 -- .largecircle. No. 2 -- .largecircle.
No. 3 .largecircle. X No. 4 .largecircle. X No. 5 .largecircle. --
No. 6 .largecircle. -- No. 7 .largecircle. -- No. 8 .largecircle.
-- No. 9 .largecircle. -- No. 10 .largecircle. -- No. 11
.largecircle. -- No. 12 .largecircle. -- No. 13 .largecircle. --
No. 14 .largecircle. -- No. 15 X -- [NOTE] .largecircle.: Stopped,
X: Not stopped, --: No test
[0089] The bigger number of the ball is the bigger size, i.e., the
heavier ball. Stopping the motion of a heavier ball means that the
preparation has a higher adhesibility. As shown in the above Table
7, the patch preparation of Preparation Example 8 can stop the
heavy ball No. 14. On the other hand, the patch preparation of
Comparison Example 5 can stop only light balls up to No. 2. The
difference shows that the loose exudation of the drug solution on
the surface of the mass base greatly varies with the presence or
absence of the powder (anhydrous silicic acid). That is, it is
shown that the drug solution is hard to exude from the mass base in
the preparation by mixing the powder, and thus the adhesibility of
the preparation is not deteriorated.
[0090] The loose exudation of the drug solution as described above
in the patch preparation of Comparison Example 5 which comprises no
powder means that the drug solution which is not sufficiently
dispersed into the mass base transfers to the surface of the mass
base. However, the transfer of the drug solution to the surface
leads to a good result from the viewpoint of the release property
of the drug solution. That is, the preparation has a poor
adhesibility, but an excellent release property of the drug
solution. When the release property of the drug solution is
excellent, the transdermal absorbability of the drug also shows a
good result.
[0091] On the other hand, as shown in Preparation Example 8, the
drug solution can be absorbed and retained in the spaces within the
mass base by the addition of the powder (anhydrous silicic acid),
and thereby the patch preparation can ensure the release property
of the drug solution in addition to the improvement and retainment
of the adhesibility of the preparation. As a result, the
transdermal absorbability can be improved. For example, comparing
Preparation Example 8 with Comparison Example 5, the skin
permeability of the drugs in Preparation Example 8 after 4 hour was
about 1.3 times better than that of Comparison Example 5. As a
result, it was demonstrated that the patch preparation of
Preparation Example 8 comprising the powder led to a better balance
between the adhesibility and the release property of the drug.
Test Example 1
In Vitro Skin Permeability Test
[0092] The test to evaluate the transdermal absorbability of
oxycodone in the patch preparation of Example 3 was performed using
a Franz diffusion cell (permeable area: cm.sup.2, volume of
receptor solution: 8 mL) at the test temperature of 32.degree. C.
as follows: [0093] (1) Rat's skin: skin isolated from the abdomen
of a 5-week old Wistar rat (male) [0094] (2) Receptor solution:
physiological saline+10% ethanol [0095] (3) Concentration
measurement of the permeable drug: HPLC
[0096] The commercially available rat's abdominal frozen skin
(5-week old Wistar rat) was mounted in a vertical diffusion cell
(effective diffusion area: 1 cm.sup.2). Each sample in Table 6
(Preparation Example 8 and Comparison Example 5) was applied to the
stratum corneum side, and also physiological saline+10% ethanol
were applied to the dermic layer side. The skin permeability of the
drug was measured by HPLC to determine the cumulative permeation
amount of the drug at 2 hours and 4 hours. As a result, the
transdermal absorbability of oxycodone as shown in Table 6 was
evaluated.
Test Example 2
Test for Evaluating the Adhesibility
[0097] The adhesibility test was performed following the ball tack
test as defined by JIS. The patch preparation is deemed to have
sufficient adhesibility when stopping ball No. 4. Thus, the ball
track test was performed using ball No. 4. Preparation Examples 5-8
and Comparison Examples 3-5 were tested as test samples.
[0098] Also, Preparation Example 8 and Comparison Example 5 were
evaluated up to ball No. 15, besides ball No. 4.
Example 4
Preparation of Non-Aqueous Patch Preparation Comprising Lidocaine
Salt of Etodolac, Organic Solvent Containing Ionic Liquid, and
Powder
[0099] In the same manner as Example 3, the reagents were weighed
according to the composition (part by weight) in Table 8 below to
prepare the tape preparations comprising the lidocaine salt of
etodolac as the drug.
[0100] Specifically, etodolac-lidocaine salt was added to propylene
glycol and mixed to prepare the drug solution. Following the
conventional solvent method using toluene as a solvent, diethyl
sebacate, butylhydroxyltoluene, terpene resin,
styrene-isoprene-styrene copolymer, and liquid paraffin were
dissolved in toluene, and then the drug solution was added thereto
and mixed. Next, crystalline cellulose or light anhydrous silicic
acid was added thereto and mixed, and then each mixture was coated
on the silicone-coated PET film and dried. After removal of the
toluene, the backing was laminated to prepare the preparations.
[0101] As with Example 3, the in vitro skin permeability test of
etodolac and the test for evaluating the adhesibility of the
prepared patch preparations were performed. The results are also
shown in Table 8.
TABLE-US-00008 TABLE 8 Preparation Preparation Example 9 Example 10
Etodolac-Lidocaine Salt 4.4 4.4 Organic Solvent: Propylene glycol 4
4 Diethyl Sebacate 4 4 Antioxidant: Butylhydroxytoluene 1 1
Lipophilic Mass Base: Terpene Resin 20 20 Styrene-Isoprene-Styrene
40 42 Block Copolymer Liquid Paraffin 20.6 19.6 Powder: Light
Anhydrous Silicic Acid 4 Crystalline Cellulose 7 Skin Permeation
Amount 20.7 25.6 (.mu.g/cm.sup.2/6 hr) Adhesibility Test, Stopping
of Stopping Stopping Ball No. 4
[0102] As shown in the above Table 8, the patch preparations of
Preparation Examples 9 and 10 can produce a better transdermal
absorbability of etodolac as well as a better adhesibility by the
addition of the powder.
Example 5
Preparation of Non-Aqueous Patch Preparation Comprising Calcitonin,
Organic Solvent Containing Ionic Liquid, and Powder
[0103] In the same manner as Example 3, the reagents were weighed
according to the composition (part by weight) in Table 9 below to
prepare the tape preparations comprising calcitonin as the
drug.
[0104] Calcitonin salmon was dissolved in triethanolamine
levulinate or triethanolamine lactate, and then triethanolamine
isostearate, macrogol 400, propylene carbonate, and propylene
glycol were added thereto and mixed to prepare each drug solution.
Following the conventional solvent method using toluene as a
solvent, diethyl sebacate, terpene resin, styrene-isoprene-styrene
copolymer, and liquid paraffin were dissolved in toluene, and then
the drug solution was added thereto and mixed. Next, corn starch,
crystalline cellulose or light anhydrous silicic acid was added
thereto and mixed, and then each mixture was coated on the
silicone-coated PET film and dried. After removal of the toluene,
the backing was laminated to prepare the preparations.
TABLE-US-00009 TABLE 9 Preparation Preparation Example 11 Example
12 Calcitonin 10.1 0.1 Ionic Liquid: Triethanolamine Levulinate 4
Triethanolamine Lactate 4 Triethanolamine Isostearate 2 3 Organic
Solvent: Macrogol 400 9 7 Propylene Carbonate 3 7 Propylene Glycol
8 5 Diethyl Sebacate 3 4 Lipophilic Mass Base:
Styrene-Isoprene-Styrene 16 16 Block Copolymer Terpene Resin 35 36
Liquid Paraffin 11.9 12.9 Powder: Starch 8 Light Anhydrous Silicic
Acid 5
[0105] The adhesibility and drug-transdermal-absorbability of the
patch preparations of Preparation Examples 11 and 12 can be
improved by the addition of the powder.
Example 6
Preparation of Non-Aqueous Patch Preparation Comprising
Agomelatine, Organic Solvent Containing Ionic Liquid, and
Powder
[0106] In the same manner as Example 3, the reagents were weighed
according to the composition (part by weight) in Table 10 below to
prepare the tape preparations comprising agomelatine as the
drug.
[0107] Specifically, agomelatine was added to the ionic liquid and
mixed to prepare the drug solution. Following the conventional
solvent method using toluene as a solvent, the organic solvent, the
antioxidant, the lipophilic mass base, and the drug solution were
mixed. Next, crystalline cellulose and light anhydrous silicic acid
were added thereto and mixed, and then each mixture was coated on
the silicone-coated PET film and dried. After removal of the
toluene, the backing was laminated to prepare the preparations.
[0108] As with Example 3, the in vitro skin permeability test was
performed on the prepared patch preparations. The results are also
shown in Table 10.
TABLE-US-00010 TABLE 10 Comparison Preparation Example 6 Example 13
Agomelatine 1.0 1.0 Ionic Liquid: Triethanolamine Isostearate 2.5
2.5 Triethanolamine Lactate 1.5 1.5 Organic Sovent: Isopropyl
Myristate 3.8 3.8 Propyl Carbonate 6.0 5.0 Polyethylene glycol 6.0
5.0 Kollidon K90 0.5 0.5 Oleic Acid 1.9 1.9 Antioxidant:
Butylhydroxytoluene 1.0 1.0 Lipophilic Mass Base: Terpene Resin
36.3 35.3 Styrene-Isoprene-Styrene Block 20.0 19.0 Copolymer Liquid
Paraffin 19.5 19.5 Powder: Light Anhydrous Silicic Acid 1.0
Crystalline Cellulose 3.0 Skin Permeation Amount (.mu.g/cm.sup.2/6
hr) 9.1 26.7
[0109] As shown in the above results of Preparation Examples 13 and
14, the transdermal absorbability of agomeltatine in the patch
preparation comprising the powder could be improved by about 3
times.
[0110] In addition, the measured residual ratio of the drug in the
preparation was 40%. As a result, it was shown that the preparation
example produced an excellent effect that about 60% of the drug
used was transdermally absorbed.
INDUSTRIAL APPLICABILITY
[0111] The non-aqueous patch preparation of the present invention
comprising a powder ingredient has the improved adhesibility since
the powder ingredient can make spaces in a lipophilic mass base,
wherein a drug solution is retained once and then gradually
released. In addition, both of the adhesibility of the patch
preparation and the release property of the drug solution, which
are conflicting factors in normal tape preparations, can be
improved in the present invention, and thus the transdermal
absorbability of the drug can also be maintained and improved.
Thus, the patch preparation of the present invention has an
excellent adhesibility to the skin and further an improved
transdermal absorbability of the drug. Also, the patch preparation
can sustainedly release the drug since the drug solution is
gradually released from the spaces beteween the powders. As a
result, the present invention has made it possible to expand the
use to new ones (the expansion of the intended drugs) in the
non-aqueous patch preparation comprising an ionic liquid, and thus
has also made it possible to expand the possibility of treating
diseases with the patch preparation.
* * * * *